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Full-Text Articles in Medicine and Health Sciences
A Self-Lysis Pathway That Enhances The Virulence Of A Pathogenic Bacterium, Kirsty A. Mcfarland, Emily L. Dolben, Michele Leroux, Tracy K. Kambara, Kathryn Ramsey, Robin Kirkpatrick, Joseph Mougous, Deborah Hogan, Simon Dove
A Self-Lysis Pathway That Enhances The Virulence Of A Pathogenic Bacterium, Kirsty A. Mcfarland, Emily L. Dolben, Michele Leroux, Tracy K. Kambara, Kathryn Ramsey, Robin Kirkpatrick, Joseph Mougous, Deborah Hogan, Simon Dove
Dartmouth Scholarship
In mammalian cells, programmed cell death (PCD) plays important roles in development, in the removal of damaged cells, and in fighting bacterial infections. Although widespread among multicellular organisms, there are relatively few documented instances of PCD in bacteria. Here we describe a potential PCD pathway in Pseudomonas aeruginosa that enhances the ability of the bacterium to cause disease in a lung infection model. Activation of the system can occur in a subset of cells in response to DNA damage through cleavage of an essential transcription regulator we call AlpR. Cleavage of AlpR triggers a cell lysis program through de-repression of …
Nonreplicating, Cyst-Defective Type Ii Toxoplasma Gondii Vaccine Strains Stimulate Protective Immunity Against Acute And Chronic Infection, Barbara Andrea Fox, David J. Bzik
Nonreplicating, Cyst-Defective Type Ii Toxoplasma Gondii Vaccine Strains Stimulate Protective Immunity Against Acute And Chronic Infection, Barbara Andrea Fox, David J. Bzik
Dartmouth Scholarship
Live attenuated vaccine strains, such as type I nonreplicating uracil auxotroph mutants, are highly effective in eliciting lifelong immunity to virulent acute infection by Toxoplasma gondii. However, it is currently unknown whether vaccine-elicited immunity can provide protection against acute infection and also prevent chronic infection. To address this problem, we developed nonreverting, nonreplicating, live attenuated uracil auxotroph vaccine strains in the type II Δku80 genetic background by targeting the deletion of the orotidine 5′-monophosphate decarboxylase (OMPDC) and uridine phosphorylase (UP) genes. Deletion of OMPDC induced a severe uracil auxotrophy with loss of replication, loss of …
Epoxide-Mediated Differential Packaging Of Cif And Other Virulence Factors Into Outer Membrane Vesicles, A. E. Ballok, L. M. Filkins, J.. M. Bomberger, B. A. Stanton, George A. O'Toole
Epoxide-Mediated Differential Packaging Of Cif And Other Virulence Factors Into Outer Membrane Vesicles, A. E. Ballok, L. M. Filkins, J.. M. Bomberger, B. A. Stanton, George A. O'Toole
Dartmouth Scholarship
Pseudomonas aeruginosa produces outer membrane vesicles (OMVs) that contain a number of secreted bacterial proteins, including phospholipases, alkaline phosphatase, and the CFTR inhibitory factor (Cif). Previously, Cif, an epoxide hydrolase, was shown to be regulated at the transcriptional level by epoxides, which serve as ligands of the repressor, CifR. Here, we tested whether epoxides have an effect on Cif levels in OMVs. We showed that growth of P. aeruginosa in the presence of specific epoxi
Pouring Salt On A Wound: Pseudomonas Aeruginosa Virulence Factors Alter Na+ And Cl− Flux In The Lung, Alicia E. Ballok, George A. O'Toole
Pouring Salt On A Wound: Pseudomonas Aeruginosa Virulence Factors Alter Na+ And Cl− Flux In The Lung, Alicia E. Ballok, George A. O'Toole
Dartmouth Scholarship
Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen with multiple niches in the human body, including the lung. P. aeruginosa infections are particularly damaging or fatal for patients with ventilator-associated pneumonia, chronic obstructive pulmonary disease, and cystic fibrosis (CF). To establish an infection, P. aeruginosa relies on a suite of virulence factors, including lipopolysaccharide, phospholipases, exoproteases, phenazines, outer membrane vesicles, type III secreted effectors, flagella, and pili. These factors not only damage the epithelial cell lining but also induce changes in cell physiology and function such as cell shape, membrane permeability, and protein synthesis. While such virulence factors are important in …
Anr And Its Activation By Plch Activity In Pseudomonas Aeruginosa Host Colonization And Virulence, Angelyca A. Jackson, Maegan J. Gross, Emily F. Daniels, Thomas H. Hampton, John H. Hammond, Isabelle Vallet-Gely, Simon L. Dove, Bruce A. Stanton, Deborah A. Hogan
Anr And Its Activation By Plch Activity In Pseudomonas Aeruginosa Host Colonization And Virulence, Angelyca A. Jackson, Maegan J. Gross, Emily F. Daniels, Thomas H. Hampton, John H. Hammond, Isabelle Vallet-Gely, Simon L. Dove, Bruce A. Stanton, Deborah A. Hogan
Dartmouth Scholarship
Pseudomonas aeruginosa hemolytic phospholipase C (PlcH) degrades phosphatidylcholine (PC), an abundant lipid in cell membranes and lung surfactant. A ΔplcHR mutant, known to be defective in virulence in animal models, was less able to colonize epithelial cell monolayers and was defective in biofilm formation on plastic when grown in lung surfactant. Microarray analyses found that strains defective in PlcH production had lower levels of Anr-regulated transcripts than the wild type. PC degradation stimulated the Anr regulon in an Anr-dependent manner under conditions where Anr activity was submaximal because of the presence of oxygen. Two PC catabolites, choline and glycine …
Characterization Of Vibrio Cholerae O1 El Tor Biotype Variant Clinical Isolates From Bangladesh And Haiti, Including A Molecular Genetic Analysis Of Virulence Genes, Mike S. Son, Christina J. Megli, Gabriela Kovacikova, Firdausi Qadri, Ronald K. Taylor
Characterization Of Vibrio Cholerae O1 El Tor Biotype Variant Clinical Isolates From Bangladesh And Haiti, Including A Molecular Genetic Analysis Of Virulence Genes, Mike S. Son, Christina J. Megli, Gabriela Kovacikova, Firdausi Qadri, Ronald K. Taylor
Dartmouth Scholarship
Vibrio cholerae serogroup O1, the causative agent of the diarrheal disease cholera, is divided into two biotypes: classical and El Tor. Both biotypes produce the major virulence factors toxin-coregulated pilus (TCP) and cholera toxin (CT). Although possessing genotypic and phenotypic differences, El Tor biotype strains displaying classical biotype traits have been reported and subsequently were dubbed El Tor variants. Of particular interest are reports of El Tor variants that produce various levels of CT, including levels typical of classical biotype strains. Here, we report the characterization of 10 clinical isolates from the International Centre for Diarrhoeal Disease Research, Bangladesh, and …
Whole-Genome Sequencing Of Staphylococcus Aureus Strain Rn4220, A Key Laboratory Strain Used In Virulence Research, Identifies Mutations That Affect Not Only Virulence Factors But Also The Fitness Of The Strain, Dhanalakshmi Nair, Guido Memmi, David Hernandez, Jonathan Bard, Marie Beaume, Steven Gill, Patrice Francois, Ambrose L. Cheung
Whole-Genome Sequencing Of Staphylococcus Aureus Strain Rn4220, A Key Laboratory Strain Used In Virulence Research, Identifies Mutations That Affect Not Only Virulence Factors But Also The Fitness Of The Strain, Dhanalakshmi Nair, Guido Memmi, David Hernandez, Jonathan Bard, Marie Beaume, Steven Gill, Patrice Francois, Ambrose L. Cheung
Dartmouth Scholarship
Staphylococcus aureus RN4220, a cloning intermediate, is sometimes used in virulence, resistance, and metabolic studies. Using whole-genome sequencing, we showed that RN4220 differs from NCTC8325 and contains a number of genetic polymorphisms that affect both virulence and general fitness, implying a need for caution in using this strain for such studies.
The Staphylococcus-Specific Gene Rsr Represses Agr And Virulence In Staphylococcus Aureus, Sandeep Tamber, Dindo Reyes, Niles P. Donegan, Joseph D. Schwartzman, Ambrose L. Cheung, Guido Memmi
The Staphylococcus-Specific Gene Rsr Represses Agr And Virulence In Staphylococcus Aureus, Sandeep Tamber, Dindo Reyes, Niles P. Donegan, Joseph D. Schwartzman, Ambrose L. Cheung, Guido Memmi
Dartmouth Scholarship
The expression of virulence factors in Staphylococcus aureus is tightly coordinated by a vast network of regulatory molecules. In this report, we characterize a genetic locus unique to staphylococci called rsr that has a role in repressing two key virulence regulators, sarR and agr. Using strain SH1000, we showed that the transcription of virulence effectors, such as hla, sspA, and spa, is altered in an rsr mutant in a way consistent with agr upregulation. Analysis of RNAIII expression of the agr locus in rsr and rsr-sarR mutants indicated that rsr likely contributes to agr expression independently …
Role Of Pknb Kinase In Antibiotic Resistance And Virulence In Community-Acquired Methicillin-Resistant Staphylococcus Aureus Strain Usa300, S. Tamber, J. Schwartzman, A. L. Cheung
Role Of Pknb Kinase In Antibiotic Resistance And Virulence In Community-Acquired Methicillin-Resistant Staphylococcus Aureus Strain Usa300, S. Tamber, J. Schwartzman, A. L. Cheung
Dartmouth Scholarship
The regulation of cellular processes by eukaryote-like serine/threonine kinases is widespread in bacteria. In the last 2 years, several studies have examined the role of serine/threonine kinases in Staphylococcus aureus on cell wall metabolism, autolysis, and virulence, mostly in S. aureus laboratory isolates in the 8325-4 lineage. In this study, we showed that the pknB gene (also called stk1) of methicillin-resistant S. aureus (MRSA) strain COL and the community-acquired MRSA (CA-MRSA) strain USA300 is involved in cell wall metabolism, with the pknB mutant exhibiting enhanced sensitivity to β-lactam antibiotics but not to other classes of antibiotics, including aminoglycosides, ciprofloxacin, …
Crystal Structure Of The Cystic Fibrosis Transmembrane Conductance Regulator Inhibitory Factor Cif Reveals Novel Active-Site Features Of An Epoxide Hydrolase Virulence Factor, Christopher D. Bahl, Christophe Morisseau, Jennifer M. Bomberger, Bruce A. Stanton, Bruce D. Hammock, George A. O'Toole, Dean R. Madden
Crystal Structure Of The Cystic Fibrosis Transmembrane Conductance Regulator Inhibitory Factor Cif Reveals Novel Active-Site Features Of An Epoxide Hydrolase Virulence Factor, Christopher D. Bahl, Christophe Morisseau, Jennifer M. Bomberger, Bruce A. Stanton, Bruce D. Hammock, George A. O'Toole, Dean R. Madden
Dartmouth Scholarship
Cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is a virulence factor secreted by Pseudomonas aeruginosa that reduces the quantity of CFTR in the apical membrane of human airway epithelial cells. Initial sequence analysis suggested that Cif is an epoxide hydrolase (EH), but its sequence violates two strictly conserved EH motifs and also is compatible with other alpha/beta hydrolase family members with diverse substrate specificities. To investigate the mechanistic basis of Cif activity, we have determined its structure at 1.8-A resolution by X-ray crystallography. The catalytic triad consists of residues Asp129, His297, and Glu153, which are conserved across the …
A Vibrio Cholerae Classical Tcpa Amino Acid Sequence Induces Protective Antibody That Binds An Area Hypothesized To Be Important For Toxin-Coregulated Pilus Structure, Ronald K. Taylor, Thomas J. Kirn, Michael D. Meeks, Terri K. Wade, William F. Wade
A Vibrio Cholerae Classical Tcpa Amino Acid Sequence Induces Protective Antibody That Binds An Area Hypothesized To Be Important For Toxin-Coregulated Pilus Structure, Ronald K. Taylor, Thomas J. Kirn, Michael D. Meeks, Terri K. Wade, William F. Wade
Dartmouth Scholarship
Vibrio cholerae is a gram-negative bacterium that has been associated with cholera pandemics since the early 1800s. Whole-cell, killed, and live-attenuated oral cholera vaccines are in use. We and others have focused on the development of a subunit cholera vaccine that features standardized epitopes from various V. cholerae macromolecules that are known to induce protective antibody responses. TcpA protein is assembled into toxin-coregulated pilus (TCP), a type IVb pilus required for V. cholerae colonization, and thus is a strong candidate for a cholera subunit vaccine. Polypeptides (24 to 26 amino acids) in TcpA that can induce protective antibody responses have …
Saru, A Sara Homolog, Is Repressed By Sart And Regulates Virulence Genes In Staphylococcus Aureus, Adhar C. Manna, Ambrose L. Cheung
Saru, A Sara Homolog, Is Repressed By Sart And Regulates Virulence Genes In Staphylococcus Aureus, Adhar C. Manna, Ambrose L. Cheung
Dartmouth Scholarship
In searching the Staphylococcus aureus genome, we previously identified sarT, a homolog of sarA, which encodes a repressor for alpha-hemolysin synthesis. Adjacent but transcribed divergently to sarT is sarU, which encodes a 247-residue polypeptide, almost twice the length of SarA. Sequence alignment disclosed that SarU, like SarS, which is another SarA homolog, could be envisioned as a molecule with two halves, with each half being homologous to SarA. SarU, as a member of the SarA family proteins, disclosed conservation of basic residues within the helix-turn-helix motif and within the beta hairpin loop, two putative DNA binding domains within this protein …
Clinical And Epidemiological Correlates Of Genotypes Within The Mycobacterium Avium Complex Defined By Restriction And Sequence Analysis Of Hsp65, Sandra C. Smole, Fionnuala Mcaleese, Jutamas Ngampasutadol, C. Fordham Von Reyn, Robert D. Arbeit
Clinical And Epidemiological Correlates Of Genotypes Within The Mycobacterium Avium Complex Defined By Restriction And Sequence Analysis Of Hsp65, Sandra C. Smole, Fionnuala Mcaleese, Jutamas Ngampasutadol, C. Fordham Von Reyn, Robert D. Arbeit
Dartmouth Scholarship
Species identification of isolates of the Mycobacterium avium complex (MAC) remains a difficult task. Although M. avium and Mycobacterium intracellulare can be identified with expensive, commercially available probes, many MAC isolates remain unresolved, including those representing Mycobacterium lentiflavum as well as other potentially undefined species. PCR restriction analysis (PRA) of the hsp65 gene has been proposed as a rapid and inexpensive approach. We applied PRA to 278 MAC isolates, including 126 from blood of human immunodeficiency virus (HIV)-infected patients, 59 from sputum of HIV-negative patients with chronic obstructive pulmonary disease, 88 from environmental sources, and 5 pulmonary isolates from …
Identification Of The Vibrio Cholerae Enterobactin Receptors Vcta And Irga: Irga Is Not Required For Virulence, Alexandra R. Mey, Elizabeth E. Wyckoff, Amanda G. Oglesby, Eva Rab, Ronald K. Taylor, Shelley M. Payne
Identification Of The Vibrio Cholerae Enterobactin Receptors Vcta And Irga: Irga Is Not Required For Virulence, Alexandra R. Mey, Elizabeth E. Wyckoff, Amanda G. Oglesby, Eva Rab, Ronald K. Taylor, Shelley M. Payne
Dartmouth Scholarship
The gram-negative enteric pathogen Vibrio cholerae requires iron for growth. V. cholerae has multiple iron acquisition systems, including utilization of heme and hemoglobin, synthesis and transport of the catechol siderophore vibriobactin, and transport of several siderophores that it does not itself make. One siderophore that V. cholerae transports, but does not make, is enterobactin. Enterobactin transport requires TonB and is independent of the vibriobactin receptor ViuA. In this study, two candidate enterobactin receptor genes, irgA (VC0475) and vctA (VCA0232), were identified by analysis of the V. cholerae genomic sequence. A single mutation in either of these genes did not significantly …
Staphylococcus Aureus Agr And Sara Functions Are Required For Invasive Infection But Not Inflammatory Responses In The Lung, Geoffrey Heyer, Shahryar Saba, Robert Adamo, William Rush, Grace Soong, Ambrose Cheung, Alice Prince
Staphylococcus Aureus Agr And Sara Functions Are Required For Invasive Infection But Not Inflammatory Responses In The Lung, Geoffrey Heyer, Shahryar Saba, Robert Adamo, William Rush, Grace Soong, Ambrose Cheung, Alice Prince
Dartmouth Scholarship
Staphylococcus aureus strains lacking agr- and sarA-dependent gene products or specific MSCRAMM (microbial surface components recognizing adhesive matrix molecules) adhesins were compared for the ability to activate inflammatory responses in the lung. The mutants were evaluated for virulence in a mouse model of pneumonia and by quantifying their ability to stimulate interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in respiratory epithelial cells. In a neonatal mouse, only strains with intact agr and sarA loci were consistently associated with invasive, fatal pulmonary infection (P < 0.001) and sarA was specifically required to cause bacteremia (P < 0.001). The agr and/or sarA mutants were, nonetheless, fully capable of producing pneumonia and were as proficient as the wild-type strain in stimulating epithelial IL-8 expression, a polymorphonuclear leukocyte chemokine, in airway cells. In contrast, agr and especially sarA mutants induced less epithelial GM-CSF expression, and MSCRAMM mutants lacking fibronectin binding proteins or clumping factor A, a ligand for fibrinogen, were unable to stimulate epithelial GM-CSF production. The ability to induce IL-8 expression was independent of the adherence properties of intact bacteria, indicating that shed and/or secreted bacterial components activate epithelial responses. While conserved staphylococcal components such as peptidoglycan are sufficient to evoke inflammation and cause pneumonia, the agr and sarA loci of S. aureus are critical for the coordination of invasive infection of the lungs.